DESCRIPTION (applicant's abstract): The proposed research will test the hypothesis that neurotrophins act as neuromodulators in the mechanisms responsible for the generation and maintenance of REM sleep. The experiments are based upon three findings: first, that the microinjection of NGF into the nucleus pontis oralis (NPO) produces long-lasting episodes of REM sleep (Yamuy, et al., 1995a); second, that neurotrophins and neurotrophin receptors are present in neurons located in regions that are implicated in the generation of this behavioral state (Yamuy et al., 1997a, b); and third, that a larger number of neurons that contain neurotrophin receptors are activated (i.e., express the proto-oncogene c-fos) in the NPO during NGF- and carbachol-induced REM sleep than during wakefulness (Yamuy et al., 1997b). First, behavioral studies in chronically-prepared cats will be employed to: a) determine whether the blockade of neurotrophin receptor mechanisms produces changes in neurotrophin-induced and natural REM sleep, and b) determine whether the blockade of neurotrophin synthesis in neurons of the lateral-dorsal and pedunculo-pontine tegmental nuclei produces a decrease in the occurrence of REM sleep. Second, immunocytochemical studies will be conducted in ponto-mesencephalic sections to determine whether neurons that contain neurotrophins and/or neurotrophin receptors belong to neurochemical types (cholinergic, noradrenergic, and serotonergic) that are implicated in the regulation of REM sleep. Third, intracellular and extracellular recording techniques in combination with juxtacellular application of drugs and intracellular marking will be carried out in vivo to determine the effects of neurotrophins on the electrical properties of pontine neurons and establish a foundation to understand the subcellular mechanisms responsible for these effects. Whereas the behavioral studies will disclose a physiologic role for these trophic factors in the generation of REM sleep, the immunocytochemical studies will shed light on the anatomical relationship between the "neurotrophinergic" system and the neurotransmitter systems classically implicated in REM sleep regulation. Finally, the electrophysiological studies will explore the rapid effects of neurotrophins on the excitability of identified, individual, pontine neurons. This concerted set of experiments will be critical in elucidating the role that neurotrophins play in the control of REM sleep.